Systemic fungal infections are of increasing importance because of continued and expanded use of immunosuppresive therapies, antimicrobial therapies and indwelling catheters. Currently there are limited therapies available to treat such fungal infections. Amphotericin B remains the drug of choice because it has the widest spectrum of antifungal activity of any systemic antifungal drug, however its utility is limited by its toxicity. Because of the potential seriousness of its toxic effects, intravenous use of amphotericin B is primarily for patients with progressive, potentially fatal infections in which the patient is hospitalized during the course of therapy. Thus, there is a continuing need to develop safer and more effective drugs which are useful for the treatment of fungal infections.
Plant pathogenic fungi and other disease incitants also cause extensive losses in crops annually. While there are commercially available materials used to control many plant diseases, further improvement in this art is needed if full food and fiber production is to be realized.
There are a large number of patent and literature references in the area of azole antifungal drugs and plant disease control agents. Most pertinent to the .alpha.-styryl carbinol compounds of this invention are the following references:
B. Sugavanam in U.S. Pat. No. 4,507,140 issued Mar. 26, 1985 discloses fungicidal or plant growth regulating .beta.-styryl triazoles or imidazoles, amongst others of the formula: ##STR2## where R.sup.1 is CH.dbd.CH--X; --C.tbd.C--X or --CH.sub.2 --CH.sub.2 --X;
X is substituted aryl, aralkyl, or heterocycle; PA0 R.sup.2 is alkyl, cycloalkyl, or optionally substituted aryl; PA0 Z is OR.sup.3 ; PA0 R.sup.3 is H, acetyl; PA0 Y is --N-- or --CH--. PA0 X is N, or a CH group; PA0 Y is --OCH.sub.2 --, --CH.sub.2 CH.sub.2 -- or CH.dbd.CH; PA0 Z is halogen, alkyl, cycloalkyl, alkoxy, alkylthio, etc. PA0 X is --OCH.sub.2 --, --SCH.sub.2 --, --(CH.sub.2).sub.p or --CH.dbd.CH--; PA0 Z is halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, or haloalkylthio; PA0 m and p are 0, 1 and 2. PA0 Q is imidazoyl or 1H- or 4H-1,2,4-triazol-1-yl; PA0 R.sup.1 is H, 1-5C alkyl, or 1-8C acyl; PA0 R.sup.2 and R.sup.3 are 1-5C alkyl, 3-6C cycloalkyl, 2-6C alkenyl, benzyl (optionally substituted by 1-3 halogen), pyridyl, furyl, thienyl, or phenyl optionally substituted by 1-3 halogen, 1-3 alkyl, or 1-3C alkoxy. PA0 R.sub.3 =H or lower alkyl; PA0 R.sub.4 and R.sub.5 =H or halo; PA0 Y=CH or N; PA0 A=2-7C alkylene; PA0 n=0 or 1. PA0 A is perfluoroalkyl of 1-8 carbon atoms, N(CH.sub.3).sub.2, OH, naphthyl optionally substituted with a total of 1-3 substituents each of which is independently selected from halogen and CF.sub.3, ##STR9## optionally substituted with 1 or 2 methyl groups, phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from: PA0 B is alkyl of 1-8 carbon atoms, naphthyl, biphenyl, ##STR11## perfluoroalkyl of 1-8 carbon atoms, phenyl optionally substituted with 1-3 substituents each of which is independently selected from: halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, and with no more than one group selected from haloalkoxy of 1-4 carbon atoms, CN, CO.sub.2 R.sub.14, CH.dbd.NOR.sub.14, S(O).sub.m R.sup.5, 2-,3-,4-pyridyl or an N-oxide thereof, PA0 Q is H, halogen, S(O).sub.m R.sup.11, ##STR12## CO.sub.2 R.sup.13, SCN, SSR.sup.12, or SH or its corresponding disulfide, provided however that when Q is other than H, then n is 0, R, R.sup.1, and R.sup.4 are independently H or CH.sub.3, R.sup.3 is H, and A and B are each phenyl optionally substituted with from 1-3 substituents each of which is independently halogen, CH.sub.3, CF.sub.3, OCH.sub.3, or S(O).sub.m R.sup.5 ; PA0 L is CH or N with the proviso that when L=CH then Q=H; PA0 n is 0-4 with the proviso that when A is ##STR13## N(CH.sub.3).sub.2, or OH, then n is other than 0; m each occurrence is 0, 1 or 2; PA0 X is C, NR.sup.10, or 0; PA0 R and R.sup.1 independently are H, alkyl of 1-4 carbon atoms, halogen, or phenyl, or taken together form cycloalkyl of 3-7 carbon atoms; PA0 R.sup.2 is H, allyl, propargyl, alkyl of 1-4 carbon atoms, ##STR14## or haloalkyl of 1-4 carbon atoms; R.sup.3 and R.sup.4 independently are H, F, or alkyl of 1-4 carbon atoms; PA0 R.sup.5 is alkyl of 1-4 carbon atoms; PA0 R.sup.6 is phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from halogen and CF.sub.3 ; PA0 R.sup.7 is alkyl of 1-4 carbon atoms, phenyl, or benzyl; PA0 R.sup.8 and R.sup.9 independently are H, alkyl of 1-4 carbon atoms, phenyl or benzyl; PA0 R.sup.10 is H, alkyl of 1-4 carbon atoms, or acetyl; PA0 R.sup.11 is alkyl of 1-4 carbon atoms, haloalkyl of 1-2 carbon atoms, CH.sub.2 CN, CH.sub.2 SCN, CH(CH.sub.3)CN, CH.sub.2 CO.sub.2 CH.sub.3, or CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3 ; PA0 R.sup.12 is alkyl of 1-4 carbon atoms, allyl, phenyl optionally substituted with 1-2 substituents each of which is independently halogen, CH.sub.3, or OCH.sub.3, or benzyl optionally substituted with 1-2 substituents each of which is independently halogen, CH.sub.3, or OCH.sub.3 ; PA0 R.sup.13 is H, or alkyl of 1-4 carbon atoms; and PA0 R.sup.14 is alkyl of 1-4 carbon atoms. PA0 E is a bond; PA0 L is N; PA0 A is perfluoroalkyl of 1-4 carbon atoms, naphthyl optionally substituted with a total of 1-2 substituents each of which is independently selected from halogen and CF.sub.3, ##STR15## optionally substituted with 1 or 2 methyl groups, phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from: PA0 B is alkyl of 1-4 carbon atoms, naphthyl, PA0 Q is H, halogen, S(O).sub.m R.sup.11, ##STR17## CO.sub.2 R.sup.13, SCN, SSR.sup.12, or SH or its corresponding disulfide, provided however that when Q is other than H, then n is 0, R, R.sup.1,and R.sup.4 are independently H or CH.sub.3, R.sup.3 is H, and A and B are each phenyl optionally substituted with from 1-3 substituents each of which is independently halogen, CH.sub.3, CF.sub.3, or OCH.sub.3 ; PA0 n is 0-2 with the proviso that when A is ##STR18## then n is other than 0; m each occurrence is 0, 1 or 2; PA0 X is C, NR.sup.10, or 0; PA0 R and R.sup.1 independently are H, alkyl of 1-2 carbon atoms, haogen, or phenyl, or taken together form cycloalkyl of 3-6 carbon atoms; PA0 R.sup.2 is H, allyl, propargyl, alkyl of 1-2 carbon atoms, ##STR19## or haloalkyl of 1-4 carbon atoms; R.sup.3 and R.sup.4 independently are H, F, or alkyl of 1-2 carbon atoms; PA0 R.sup.6 is phenyl optionally substituted with a total of 1-3 substituents each of which is independently selected from halogen and CF.sub.3 ; PA0 R.sup.7 is alkyl of 1-2 carbon atoms, phenyl, or benzyl; PA0 R.sup.8 and R.sup.9 independently are H, alkyl of 1-2 carbon atoms, phenyl or benzyl; PA0 R.sup.10 is H, alkyl of 1-2 carbon atoms, or acetyl; PA0 R.sup.11 is alkyl of 1-2 carbon atoms, haloalkyl of 1-2 carbon atoms, CH.sub.2 CN, CH.sub.2 SCN, CH(CH.sub.3)CN, CH.sub.2 CO.sub.2 CH.sub.3, or CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3 ; PA0 R.sup.12 is alkyl of 1-2 carbon atoms, allyl, phenyl optionally substituted with 1-2 substituents each of which is independently halogen, CH.sub.3, or OCH.sub.3, or benzyl optionally substituted with 1-2 substituents each of which is independently halogen, CH.sub.3, or OCH.sub.3 ; and PA0 R.sup.13 is H, or alkyl of 1-2 carbon atoms. PA0 (1) n=0, or 1; and/or PA0 (2) R.sup.3 and R.sup.4 independently are H, CH.sub.3, or F. PA0 (1) A, and B independently are phenyl optionally substituted with from 1-3 substituents each of which is halogen, alkyl of 1-4 carbon atoms, haloalkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, or S(O).sub.m R.sup.5 ; and/or PA0 (2) n=0; and/or PA0 (3) R and R.sup.1 independently are H, CH.sub.3 or halogen; and/or PA0 (4) R.sup.2 =H, alkyl of 1-4 carbon atoms, allyl, or propargyl; and/or PA0 (5) Q is H, I, SH. PA0 (1) A and B independently are phenyl optionally substituted with from 1-3 halogen atoms, CH.sub.3, OCH.sub.3, CF.sub.3, or SCH.sub.3 ; and/or; PA0 (2) R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and Q are all H. PA0 (a) 2-(4-Fluorophenyl)-3-phenyl-1-(1H-1,2,4-triazol-1-yl)-3-buten-2-ol; and the (S) enantiomer thereof. PA0 (b) 2,3-Bis(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2-ol; and the (S) enantiomer thereof. PA0 (c) 2-(2,4-Dichlorophenyl)-3-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (d) 2-(4-Chlorophenyl)-3-(2-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-ol; and the (S) enantiomer thereof. PA0 (e) 2-(2,4-Dichlorophenyl)-3-(3-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (f) 2-(2-Chlorophenyl)-3-(2-(chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2 -ol; and the (S) enantiomer thereof. PA0 (g) 2-(2,4-Dichlorophenyl)-3-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (h) 2-(4-Fluorophenyl)-3-(4-trifluoromethylphenyl)-1-(1H-1,2,4-triazol-1-yl)-3 -buten-2-ol; and the (S) enantiomer thereof. PA0 (i) 2-(2,4-Dichlorophenyl)-3-phenyl-1-(1H-1,2,4-triazol-1-yl)-3-buten-2-ol; and the (S) enantiomer thereof. PA0 (j) 2-(3,4-Dichlorophenyl)-3-(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (k) 2-(4-Chlorophenyl)-3-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2- ol; and the (S) enantiomer thereof. PA0 (l) 2-(4-Fluorophenyl)-3-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (m) 2-(2,4-Difluorophenyl)-3-(2-chlorophenyl)-(1H-1,2,4-triazol-1-yl)-3-buten- 2-ol; and the (S) enantiomer thereof. PA0 (n) 2-(2,4-Dichlorophenyl)-3-(2-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (o) 2-(2,4-Difluorophenyl)-3-phenyl)-1-(1H-imidazol-1-yl)-3-buten-2-ol; and the (S) enantiomer thereof. PA0 (p) 2-(2,4-Difluorophenyl)-3-(4-fluorophenyl)-1-(1H-imidazol-1-yl)-3-buten-2-o l; and the (S) enantiomer thereof. PA0 (q) 2-(2,4-Difluorophenyl)-3-(2-chlorophenyl)-1-(1H-imidazol-1-yl)-3-buten-2-o l; and the (S) enantiomer thereof. PA0 (r) 2-(2,4-Difluorophenyl)-3-phenyl-1-(1H-1,2,4-triazol-1-yl)-3-buten-2-ol; and the (S) enantiomer thereof. PA0 (s) 2-(2,4-Difluorophenyl)-3-(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (t) 2-(2-Fluorophenyl)-3-(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2- ol; and the (S) enantiomer thereof. PA0 (u) 2-(2-Fluorophenyl)-3-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2- ol; and the (S) enantiomer thereof. PA0 (v) 2-(2,4-Difluorophenyl)-3-(4-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-bute n-2-ol; and the (S) enantiomer thereof. PA0 (w) 2-(2-Chlorophenyl)-3-(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-buten-2- ol; and the (S) enantiomer thereof. PA0 (x) 2-(4-Chlorophenyl)-3-phenyl-1-(1H-1,2,4-triazol-1-yl)-3-buten-2-ol; and the (S) enantiomer thereof.
German Patent No. 3,018,865, published May 16, 1980 discloses antimycotic agents of the formula: ##STR3## where amongst others R is alkyl, optionally substituted cycloalkyl or optionally substituted phenyl radical;
German Patent No. 3,314,548-A, published Apr. 21, 1983 discloses substituted 1-hydroxy-ethyl-triazole derivatives of the formula: ##STR4## where amongst others R is alkyl, cycloalkyl or phenyl optionally substituted;
The compounds are antimycotics for treating dermatophytomycoses and systemic mycoses caused, e.g., by Candida sp., Aspergillus sp., Trichophyton sp.
The above three references, which pertain to .beta.-styryl azoles, are believed to be the most relevant. The .beta.-styryl azole analog of one of the preferred compounds of the instant invenstion was prepared and found to be significantly less active.
European Patent Application No. 114,487 which published Aug. 1, 1984 discloses azolylethanol derivatives of the formula: ##STR5##
Where amongst others R.sup.1 and R.sup.2 which may be the same or different are hydrogen, alkyl, cycloalkyl, alkenyl, heterocyclyl aryl, or aralkyl optionally substituted; W is N or CH; and X is C.dbd.O. The compounds have fungicidal activity and plant growth regulating activity.
European Patent No. 117,578-A, published Feb. 23, 1984 discloses heterocyclic-hydroxy-alkyl alkyl ketone(s) and analogues of the formula: ##STR6## where A is CO amongst others;
Belgian Patent No. 900,594-A published Sept. 22, 1983 discloses 1-phenyl-1-azolyl-hydroxyethyl cycloalkane derivatives of the formula: ##STR7## where R.sub.1 and R.sub.2 =H, halo, NO.sub.2, lower alkyl, alkenyl, alkynyl, alkoxy or alkylthio (all optionally substituted by 1 or more halo), or optionally substituted phenyl or phenoxy;
The compounds are useful as agricultural fungicides and antimycotics.
None of the cited references nor any known references suggest the novel antifungal compounds of this invention.